Project Summary: Leishmaniasis is a tropical disease caused by obligate intracellular protozoan parasites (1). Over 12 million people are currently infected worldwide, and the number of new cases is rising each year. Currently there is no vaccine available and treatments are often prohibitively expensive in regions where disease is endemic. Visceral leishmaniasis (VL) is the most clinically severe manifestation of disease, and is often fatal in the absence of treatment (2). In VL, parasites actively replicate within phagocytic cells of the liver, spleen and bone marrow. CD4+ T helper cell type I (Thi) responses associated with interferon (IFN)-gamma and interieukin (IL)-12 production are key in the control and resolution of hepatic disease (4). IL-12 drives the differentiation of IFN-gamma-producing Thi cells, and IFN-gamma then activates infected phagocytes to kill intracellular parasites (6, 7). Therefore, it was very surprising. to find that mice lacking signal transducer and activator of transcription-1 (STATI) ~ a transcripition factor involved in IFN-gamma signaling and the differentiation of naive T cells into Thi cells ~ are higtily resistant to disease from very early time points post-infection. Although STATI-deficient (STATI- /-) mice recruit significantly fewer T cells and phagocytes into the the liver following infection, adoptive transfer studies showed that STATI signaling in T cells does not mediate disease susceptibility (16). Preliminary studies investigating the role of phagocytes during VL found that macrophages contribute to disease pathology, and phagocytes from STATI-/- mice have significant impairments in parasite uptake. Therefore it is hypothesized that STATI signaling in phagocytes enhances susceptibility to VL. In order to test this hypothesis this proposal aims to: determine if phagocytes of STATI-/- mice exhibit differences in in vitro phagocytosis and chemotaxis;and to characterize early in vivo immune responses in wild-type and STATI-deficient mice infected with VL. Public Health Relevance: Over 350 million people are currently at risk of acquiring leishmaniasis worldwide, and with the number of new cases rising each year, emerging drug resistance and the lack of a vaccine, leishmaniasis represents a major global health problem2. Research that will lead to a better understanding of the immune responses involved in combating leishmaniasis is critical for the development of future prevention and treatment strategies that will alleviate and/or eliminate disease burden. In addition, research on STATI, a protein involved in host defense, will have broad implications in understanding other infectious and inflammatory diseases.